Catalytic activation of silylated nucleophiles using tBu-P4 as a base

Article abstract of DOI:10.1002/ejoc.200500087

Trialkylsilyl groups play an important role as effective protecting groups in organic synthesis. Various O, N, and C nucleophilic sites can be protected by trialkylsilyl groups to control the selectivity of reactions. The nucleophilic attack of a fluoride anion on a silyl group is recognized as one of the most useful methods for desilylation. The activation of the nucleophile-silicon bond is important not only for desilylation but also for the generation of a reactive nucleophilic anion to achieve a new bond formation. The phosphazene bases developed by Schwesinger are known to be strong non-metallic organic bases. Among them, the tBu-P4 base has been used for various selective deprotonative transformations, although the ability of tBu-P4 base to activate silylated nucleophiles has not yet been shown. A novel catalytic activation of various O, N, and C nucleophile-silicon bonds using tBu-P4 base was investigated to perform nucleophilic reactions with various electrophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200500087

SHORT COMMUNICATION
Catalytic Activation of Silylated Nucleophiles Using tBu-P4 as a Base
Masahiro Ueno,[a] Chieko Hori,[a] Koichi Suzawa,[a] Masashi Ebisawa,[a] and
Yoshinori Kondo*[a]
Keywords: Anions / Aromatic compounds / Catalysis / Phosphazenes
Trialkylsilyl groups play an important role as effective pro-
tecting groups in organic synthesis. Various O, N, and C nu-
cleophilic sites can be protected by trialkylsilyl groups to
control the selectivity of reactions. The nucleophilic attack of
a fluoride anion on a silyl group is recognized as one of the
most useful methods for desilylation. The activation of the
nucleophile–silicon bond is important not only for desi-
lylation but also for the generation of a reactive nucleophilic
anion to achieve a new bond formation. The phosphazene
bases developed by Schwesinger are known to be strong
non-metallic organic bases. Among them, the tBu-P4 base
has been used for various selective deprotonative transfor-
mations, although the ability of tBu-P4 base to activate si-
lylated nucleophiles has not yet been shown. A novel cata-
lytic activation of various O, N, and C nucleophile–silicon
bonds using tBu-P4 base was investigated to perform nucleo-
philic reactions with various electrophiles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Trialkylsilyl groups play a very important role as effective
protecting groups in organic synthesis.[1] Various O, N, and
C nucleophilic sites can be protected by trialkylsilyl groups
to control the selectivity of reactions. Various methods for
desilylation have been investigated, and the nucleophilic at-
tack of fluoride anion on a silyl group is recognized as one
of the most useful.[2] The activation of nucleophile–silicon
bonds is important not only for desilylation but also for
the generation of reactive nucleophilic anion to achieve new
bond formation. During the course of our recent studies on
base-promoted transformations,[3] we became interested in
the selective functionalization of silylated nucleophiles
using catalytic tBu-P4 base as a promoter.[4] A novel cata-
lytic activation of various O, N, and C nucleophile–silicon
bonds using tBu-P4 base was investigated to perform nucle-
ophilic reactions with various electrophiles (Figure 1).
The phosphazene bases developed by Schwesinger are
known to be strong non-metallic organic bases.[5] Among
them, tBu-P4 base shows extremely high basicity (pKBH+
= 42.1 in MeCN) and has been used for various selective
deprotonative transformations.[6] The strong affinity of tBu-
P4 base for a proton is regarded as being synthetically use-
ful, however the ability of tBu-P4 base to activate silylated
nucleophiles has not been shown.[7] Therefore, various cata-
lytic reactions using silylated nucleophiles as precursors of
highly nucleophilic anions promoted by tBu-P4 base were
Figure 1. Catalytic activation of silylated nucleophiles using tBu-
P4 base.
investigated, as shown in Figure 1. Initially, the activation
of O-silylated phenols in the presence of catalytic tBu-P4
base to generate a phenoxy anion was investigated and the
nucleophilic displacement of aryl fluoride was examined.
Recently, many important aryloxylations of aryl halides
have been reported using transition metal and other heavy
metal-catalyzed reactions;[8] however, a transition-metal-
free nucleophilic substitution reaction promoted by an or-
ganic base[9] is also considered to be an attractive process.
The reaction of TMS-OPh with 2-fluoronitrobenzene was
carried out in the presence of 10 mol-% tBu-P4 base and
the reaction proceeded smoothly at room temperature to
give the biaryl ether in quantitative yield (Table 1, entry 2).
When phenol was treated with 2-fluoronitrobenzene (1,
Scheme 1) under the same reaction conditions, the yield of
the biaryl ether (2a) was only 1.6% and unreacted 2-fluoro-
nitrobenzene (1) remained in the reaction (Table 1, entry 1).
TBDMS ethers are more stable toward nucleophilic cleav-
age than TMS ethers and can be handled as stable synthetic
blocks. To our surprise, TBDMS-OPh also showed high re-
activity in spite of the steric hindrance of the TBDMS
group, and the desired biaryl 2a was obtained in 96% yield
(Table 1, entry 3).
[a] Graduate School of Pharmaceutical Sciences, Tohoku Univer-
sity,
Aobayama, Aoba-ku, Sendai 980-8578, Japan
Fax: +81-22-217-6804
E-mail: ykondo@mail.pharm.tohoku.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2005, 1965–1968
DOI: 10.1002/ejoc.200500087
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1965

M. Ueno, C. Hori, K. Suzawa, M. Ebisawa, Y. Kondo
SHORT COMMUNICATION
Table 1. Activation of trialkyl-silylated nucleophiles and nucleophilic aromatic substitution.
[a] Reaction was carried out at 100 °C. [b] Reaction was carried out at –78 °C followed by gradual warming to 10 °C. [c] Commercially
available TBAF in THF solution (trihydrate) was used.
cleophile, TMS phenylacetylene was employed to give the
phenylethynylated product 2i in 41% yield, although some
unreacted starting material still remained (Table 1, en-
try 13). Further improvement of the reaction conditions is
underway. Examples of the introduction of an alkyne moi-
Scheme 1.
ety onto an aromatic ring by nucleophilic substitution in
the absence of a transition metal catalyst are quite lim-
ited.[10]
DMSO and DMF were found to be promising solvents
The substituted aryl fluorides 3a–e react with TBDMS-
OC6H4OMe-p in the presence of 10 mol-% tBu-P4 base
(Scheme 2). Ethyl p-fluorobenzoate (3a) reacts at 80 °C to
give the biaryl ether 4a in 91% yield (Table 2, entry 1).
Other bases such as BEMP or DBU were found to be al-
most inactive (Table 2, entries 2 and 3). p-Fluorobenzoni-
trile (3b) reacts at 100 °C to give the desired product 4b in
92% yield (Table 2, entry 4). p-Fluoro(trifluoromethyl)ben-
for the reaction and the dryness of the solvent was critical
for obtaining the products in high yields. TBDMS ethers of
other phenol derivatives were tested as substrates, and the
2-tert-butyl, 2-bromo, and 2-iodo derivatives gave excellent
results in spite of the steric bulkiness of the nucleophile.
(Table 1, entries 5, 6, and 7). The tolerance of a bromo or
iodo group is very attractive for the subsequent transforma-
tion as conventional metal-catalyzed reactions do not allow
this kind of selectivity. When TBAF was employed as a cat-
alyst the reaction was very sluggish, and only a trace
amount of product was obtained (Table 1, entry 9). The re-
action of O-silylated aliphatic alcohols was found to be
slow, but when the reaction was conducted at 100 °C, 72%
yield of the product 2f was obtained (Table 1, entry 10). As
a silylated N-nucleophile, N-TMS morpholine was reacted
to give the arylamine 2g in high yield (Table 1, entry 11).
The reaction with TMS-N3 also proceeded smoothly to give
the aryl azide 2h (Table 1, entry 12). As a C-silylated nu- Scheme 2.
Table 2. Reaction of substituted aryl fluorides with TBDMS-OC6H4OMe-p.
1966
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Eur. J. Org. Chem. 2005, 1965–1968

Catalytic Activation of Silylated Nucleophiles
SHORT COMMUNICATION
zene (3c) also reacts at 100 °C to give the desired product
4c in 93% yield. Interestingly, when the reaction of o-fluo-
robromobenzene (3d) was carried out at 100 °C in DMF,
the substitution occurred only at the fluorine-substituted
position to give the bromo biaryl ether 4d exclusively in
85% yield (Table 2, entry 6). The reaction of o-iodofluorob-
enzene (3e) was also examined and the iodo biaryl ether 4e
was obtained in 43% yield (Table 2, entry 7). The reverse
and complimentary regioselectivity to transition-metal-cat-
alyzed reactions is attractive for the selective functionali-
zation of aromatic compounds.
The reaction of styrene oxide (5) with TBDMS-OPh in
the presence of 10 mol-% tBu-P4 base at 100 °C gave the
ring-opening adduct 6. The reaction of TMS-N3 with 5 in
the presence of 10 mol-% tBu-P4 base at 65 °C in THF gave
ring-opened adducts (7a and 7b) in 94% yield. The reaction
of alkynylsilane with 5 gave the enyne derivative 8; the inter-
mediary ring-opening adduct was not isolated (Scheme 3).
Scheme 5.
Phenyltrimethylsilane (14) also reacted with pivalal-
dehyde in the presence of tBu-P4 base to give the desired
alcohol 15 in 40% yield (Scheme 6). The reaction condi-
tions should be further optimized, but it is known that the
conventional fluoride anion cannot activate phenyltrimeth-
ylsilane to generate a phenyl nucleophile.[12]
Scheme 6.
The reaction of allyltrimethylsilane[13] or alkynylsilane[14]
with carbonyl compounds gave the 1,2 adducts in excellent
yields (Scheme 7).
Scheme 3.
The epoxide opening reaction was then utilized for het-
erocyclic synthesis. The TBDMS aryl ether 9, which pos-
sesses an epoxide moiety, was subjected to the cyclization
reaction in the presence of 10 mol-% tBu-P4 base; the dihy-
drobenzofuran derivative 10 was obtained in 87% yield in
the TBDMS ether form. Subsequent reaction of the cy-
clized TBDMS ether with 2-fluoronitrobenzene (1) was
achieved in one flask without isolating the TBDMS ether
to give the aryl ether 11 in 81% yield (Scheme 4).
Scheme 7.
Triethylsilane can also be activated by treatment with
tBu-P4 base and the reactions with benzaldehyde, aceto-
phenone, and benzophenone were examined. As for the re-
action of benzaldehyde, the TES ether of the reduction pro-
duct was treated with aq. AcOH to cleave the silyl ether
to give the alcohol 18a in 89% yield. In the reaction of
acetophenone and benzophenone with triethylsilane, the si-
lyl ethers 18b and 18c were obtained in 62% and 72%
yields, respectively (Scheme 8, Table 3).[15]
Scheme 8.
Scheme 4.
In summary, a unique method for activating various nu-
Other silylated C-nucleophiles can be similarly activated cleophile–silicon bonds using tBu-P4 base has been devel-
by using tBu-P4 base, and the reaction of 2-TMS-benzo- oped and catalytic bond-forming reactions of silylated nu-
thiazole (12)[11] with benzophenone gave the alcohol 13 in cleophiles accomplished. As for the reaction mechanism,
95% yield (Scheme 5).
analysis of the interaction between tBu-P4 base and silyl
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1967

M. Ueno, C. Hori, K. Suzawa, M. Ebisawa, Y. Kondo
SHORT COMMUNICATION
Table 3. Reaction of carbonyl compounds with triethylsilane.
d) I. Leito, T. Rodima, I. A. Koppel, R. Schwesinger, V. M.
Vlasov, J. Org. Chem. 1997, 62, 8479–8483; e) H. Schlaad, H.
Kukula, J. Rudloff, I. Below, Macromolecules 2001, 34, 4302–
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T. D. Nelson, R. D. Crouch, Synthesis 1996, 1031–1069; b)
J. G. Verkade, P. B. Kisanga, Tetrahedron 2003, 59, 7819–7858
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[8] For recent biaryl ether synthesis using heavy metal catalysts
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ganometallics 2003, 22, 2775–2789; b) N. Kataoka, Q. Shelby,
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[9] As a suggested example of the use of stoichiometric tBu-P4
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Oiarbide, R. Lο´pez, E. Gómez-Bengoa, Chem. Commun. 1998,
2091–2092.
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ments are necessary to identify the exact mode of the nu-
cleophile–silicon bond activation.[16] Extensive investi-
gations of the scope and limitation of the catalytic reaction
and mechanistic studies of the activation are underway.
Supporting Information Available: Experimental details and spec-
troscopic data of the products (see also the footnote on the first
page of this article).
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clarify the exact mode of activation; NMR studies are currently
underway.
Received: February 02, 2005
1968
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1965–1968